ABSTRACT Hepatocellular carcinoma (HCC) is fastest or second fastest growing cancer, in incidence, in the US, with more than 39,000 cases this year, alone. It is consistently one of the deadliest, with 5 year survivals, even with treatment, often of less than 50%. Although liver transplant can be useful, if done early, there are few, if any, medical options that result in meaningful beneficial outcomes. New therapeutics are desperately needed. This is a Phase I feasibility study to determine if the pharmacological properties of a small molecule, with striking activity against hepatocellular carcinoma (HCC) cells in vitro, in vivo and in ex vivo models, can be improved by straightforward medicinal chemistry approaches. Briefly, SQ0079 and its 3rd generation progeny, SQ35119, are aminothiazoles with potent anti HCC activity in tissue culture (CC90s of less than 100 nM for HCC, and selectivity indexes with non-cancerous liver cells of greater than 500) that appear to work via inhibition of the mTOR pathway. The promising activity, is not only in tissue culture, but in xenograft models in mice, and perhaps most compelling, against human liver tumors in explant (ex vivo) models. However, although they, (SQ35119), have high selectivity and low toxicity, they exhibit metabolic instability and other pharmacokinetic (PK) limitations. For example, SQ35119 is rapidly metabolized, and two major metabolites are identified as an ester hydrolyzed acid and oxidized amino pyrimidine, which are likely a significant contributor to its poor PK performance. In this study, we will employ several strategies to further optimize this lead structure to discover the hydrolysis resistant ester replacements and inoxidizable amino pyrimidine bioisosteres. The new SQ35119 derivatives will be tested for better metabolic stability and PK and assuring the observed selectivity and low toxicity is maintained or improved. At the end of the proposed project, more metabolically stable and more bioavailable new leads will be delivered ready for the next stage of preclinical studies